Along with the arrival of an aging society, the medical treatment for the senile has been drawing much attention. Above all, senile dementia has become a serious social problem, and various developments have been made in an attempt to provide new pharmaceuticals to cope with the problem. However, while the agents for the treatment of amnesia and dementia are effective for the improvement of peripheral symptoms such as depression, emotional disturbances, abnormal behavior, etc., they do not show definite effects on the central symptoms of dementia, such as memory disorder, disorientation, or the like. Thus, the development of medicaments which can offer dependable action and effect on these symptoms is earnestly desired.
In the meantime, prolyl endopeptidase; EC, 3.4.21.26 is known to act on peptides containing proline and specifically cleaves out the carboxyl side of the proline. Further, this enzyme is known to act on hormones and neurotransmitters such as TRH (thyrotropin-releasing hormone), substance P, neurotensin, etc. as well as on vasopressin which is supposedly concerned with learning and memory process, resulting in decomposition and inactivation of them.
In view of the foregoing, a compound possessing inhibitory activity on prolyl endopeptidase is expected to suppress decomposition and inactivation of vasopressin, etc., thereby suggesting a potential application thereof to the treatment and prevention of amnesia and demntia as an efficacious medicament which exhibits direct action on the central symptoms of dementia [See Seikagaku, 55, 831 (1983); FOLIA PHARMACOL. JAPON, 89, 243 (1987); and J. Pharmacobio-Dyn., 10, 730 (1987)] and also to suppress decomposition and inactivation of hormones and neurotransmitters such as TRH, substance P, neurotensin, etc., thereby improving various symptoms caused by the decomposition and inactivation of these substances.
Based on the motivation described above, there have been attempted to develop prolyl endopeptidase-inhibiting agents and the following derivatives are known: ##STR11## wherein A is amino-protective group and X is amino acid residue, U.S. Pat. No. 4,687,778); ##STR12## wherein Z is benzyloxycarbonyl group, EP 322765, U.S. Pat. No. 4,857,524; ##STR13## wherein n is an integer from 1 to 4, U.S. Pat. No. 4,743,616; ##STR14## wherein m is an integer from 1 to 8, U.S. Pat. No. 4,873,342; ##STR15## EP 268190; and ##STR16## wherein R is alkyl group or phenyl group which may be substituted, Y is --O--, --CO-- or --CH.sub.2 --, n is an integer of 2 or 3 and X is --S--, --CH.sub.2 -- or --CH(OH)--, Japanese Patent Unexamined Publication No. 301671/1989.
However, a compound wherein nitrile group or oxime group has been introduced to the site corresponding to the carboxyl terminal or 2-oxopyrrolidinyl group has been introduced to the site corresponding to the amino terminal as in the compounds of the present invention represented by the formula (I) has not been within the public knowledge.